Methods for the long term reduction of body fat stores, insulin resistance, hyperinsulinemia and hyperglycemia in vertebrates with a prolactin stimulatory compound

ABSTRACT

A process for the long term modification and regulation of lipid and glucose metabolism--generally to reduce obesity, insulin resistance, and hyperinsulinemia or hyperglycemia, or both (these being the hallmarks of noninsulin dependent, or Type II diabetes)--by administration to a vertebrate, animal or human, of a dopamine agonist and a prolactin stimulator. The dopamine agonist and prolactin stimulator are administered in daily dosages, respectively, at a time of day dependent on the normal circadian rhythm of fat and lean members of a similar species. Decreases in body fat deposits result by treatment of an obese species on a daily timed sequence based on circadian rhythms of the peak prolactin, or peak prolactin and peak glucocorticosteroid, blood level established for lean insulin sensitive members of a similar species. The dopamine agonist is administered at the time of, or just after the time of peak plasma prolactin concentration found in lean animals of the same species and the prolactin stimulator is administered at a time just before the plasma prolactin rhythm reaches its peak is lean animals. Insulin resistance, and hyperinsulinemia or hyperglycemia, or both, can also be controlled in humans on a long term basis by treatment corresponding to that of the treatment of obesity. The short term daily injections reset hormonal timing in the neural centers of the brain to produce long term effects.

RELATED APPLICATIONS

This is a continuation, of application Ser. No. 08/468,528, filed Jun.6, 1995, which is in turn a continuation of application Ser. No.08/249,808, filed May 26, 1994, now U.S. Pat. No. 5,554,623 which is acontinuation of application Ser. No. 07/719,745, filed Jun. 24, 1991,now U.S. Pat. No. 5,344,832, which is a continuation-in-part ofapplication Ser. No. 07/463,327 filed Jan. 10, 1990, now abandoned,which is a continuation-in-part of application Ser. No. 07/192,332 filedMay 10, 1988, now abandoned.

FIELD OF THE INVENTION

This invention relates to an improved process for the reduction invertebrates, animals or humans, of body fat stores, and reduction ofinsulin resistance, hyperinsulinemia, which is often associated withinsulin resistance, and hyperglycemia, or reduction of plasma glucose.In particular, it relates to a process requiring the timed dailyadministrations of a dopamine agonist and a prolactin stimulator atappropriate preselected times of day, and preferably also a thyroidhormone, to reduce and control over an extended period the statedpathologies which, with obesity, are pathologies characteristic of theonset of noninsulin dependent, or Type II diabetes.

BACKGROUND

In U.S. Pat. No. 4,659,715, which issued Apr. 21, 1987 to Albert H.Meier and Anthony H. Cincotta, there is disclosed a method for thereduction in vertebrate animals of body fat stores, without concomitantdecrease in muscle mass, via the administration of multiple daily dosesover prescribed periods of a profactin-inhibiting, or dopamine compound.This method, which is associated with an altered lipid metabolism,offers hope to those suffering with obesity; a serious worldwide healthproblem.

In pending U.S. application Ser. No. 463,327, now abandoned, supra,there is disclosed a method, or process, for the long term modificationand regulation of lipid metabolism in a vertebrate, animal or human, notonly to reduce obesity, but also to reduce insulin resistance, andhyperinsulinemia or hyperglycemia, or both, by administration to asubject of a prolactin-inhibiting compound, or dopamine agonist. Therole of prolactin in a vertebrate species to control these pathologies(the hallmarks of noninsulin dependent, or Type II diabetes), it wasfound, was crucial. The level of prolactin in the blood of a species istime-of-day dependent, and cyclic, its level in the blood rising andfalling at different times of day dependent on the amount of fatdeposited in the body of the subject. The phase relationships betweenthe rise and fall of prolactin which appears in the blood streams ofobese and lean subjects, respectively, are different. Administration ofthe dopamine agonist, it is disclosed, is made over a limited period ata time of day dependent on the normal circadian rhythm of fat and leanmembers, respectively, of a similar species based on the result to beachieved. Where, e.g., it is desired to reduce the body fat of asubject, decreases in body fat deposits are produced by treatment of theobese species as a timed daily sequence based on circadian rhythms ofthe peak prolactin, or peak prolactin and peak glucocorticosteroid,blood level established for lean members of a similar species. A person,whether lean or obese, showing the effects of insulin resistance, orhyperinsulinemia and/or hyperglycemia, or both insulin resistance andhyperinsulinemia and/or hyperglycemia, treated with the dopamine agonistor prolactin-inhibiting compound, in the same manner as a personsuffering with obesity, it was found would become more sensitive toinsulin, and the effects of hyperinsulinemia and/or hyperglycemia wouldbe reduced on a long term basis. Thus, insulin resistance, andhyperinsulinemia or hyperglycemia, or both, like obesity, can becontrolled in humans on a long term basis by treatments corresponding tothat for the treatment of obesity to lower fat deposits in the body ofthe subject.

Albeit the administration to obese subjects of a prolactin-inhibitingcompound on a time-of-day schedule related to a daily prolactinsecretion cycle mimicking that of a lean subject to cause the obesesubject to lose body fat, the results have proven less than 100 percenteffective. For example, in treating a large population of obese subjectsto reduce body fat during the winter months, a significant reduction inbody fat occurred in the majority of the treated patients. On the otherhand, it was observed that a lower percentage of a population of obesepatients similarly treated during the summer months showed a significantreduction in body fat. This suggests that prolactin secretions in asubject are to some extent seasonal, but equally if not more importantit suggests that better timing and control of prolactin secretions in asubject, particularly during the summer months, can improve the rendermore effective the liporegulatory nature of the treatments of reduceobesity, reduce insulin resistance, and hyperinsulinemia orhyperglycemia, or both.

OBJECTS

It is, accordingly, a primary objective of this invention to providefurther improvements in a method for the long term modification andregulation of lipid metabolism to after, phase shift and reset on a longterm, or permanent basis, circadian hormonal timing mechanisms in theneural centers of the brain.

In particular, it is an object to provide a process for resetting thecircadian neural center of vertebrate animals, including humans, toalter neural centers which stimulate and control prolactin secretion toproduce long lasting changes in the amount of body fat stores, thesensitivity of the cellular response of a species to insulin, andovercome hyperinsulinemia and/or hyperglycemia, which generallyaccompanies insulin resistance.

A more specific object is to provide a process for resetting thecircadian neural centers of animals, including humans, which regulateand control lipogenesis to decrease obesity and maintain the more normalbody fat stores of a lean animal, or lean human, on a long term basis.

A further, and equally specific object is to provide a process forresetting on a long term basis the circadian neural centers,particularly in humans, which regulate and control the sensitivity andresponsiveness of the cells to insulin, and suppress hyperinsulinemia orhyperglycermia, or both.

THE INVENTION

These objects and others are achieved in accordance with this invention,a process which embodies in addition to the administration of a dopamineagonist, e.g. L-DOPA or bromocriptine, on a timed daily basis to modifyand reset the neural circadian oscillation expressed by the prolactinrhythm (prolactin oscillation) of a vertebrate animal or human subject,or both the prolactin and glucocorticosteroid (glucocorticosteroidoscillation) rhythms of said subject, administering on a timed dailybasis at a different predetermined time of day a prolactin stimulator,e.g., metoclopramide (Reglan), in dosage amount sufficient to increasehormonal prolactin secretion in the blood of the subject to bettercontrol and regulate the prolactin rhythm, or both the prolactin andglucocorticosteroid rhythms, of the subject. Administration of thedopamine agonist, continued on a daily basis over a sufficient period oftime, as disclosed in Application Ser. No. 463,327, supra, can beemployed to increase the hyperglycemia sensitivity to insulin, reducebody fat stores, suppress hyperinsulinemia and reduce hyperglycemia in asubject, to reset long term on cessation of the daily dosages of thedopamine agonist the neural phase oscillation of the prolactin rhythm,or both the prolactin and glucocorticosteroid rhythms, in a subject; andthe administration of the dopamine agonist and additionally theprolactin stimulator at a different predetermined time of day can beemployed to control, regulate, and reset on a long term basis thesecircadian neural hormonal expression, and correct these pathologies,with higher consistency and greater effectiveness than by administrationof the dopamine agonist alone. In treating a large subject population ofobese persons, during the summer months when the success rate is lowerthan the winter months, with a dopamine agonist alone to regulate lipidmetabolism and reduce fat deposits in the bodies of these subjects,success was achieved in about 60 percent of the patients treated. Incontrast, in treating a second large subject population of obese personsover a similar period of time during the summer months with a similardopamine agonist and additionally, a prolactin stimulator, success wasachieved in about 85 percent of the population, an improvement of about25 percent. The weight loss of body fat in a group treated with both thedopamine agonist and the prolactin stimulator, measured on a weeklybasis during the period of treatment, is almost double that of the grouptreated with the dopamine agonist alone.

The efficacy of treatment with the dopamine agonist and prolactinstimulator can also be improved by daily thyroid hormone administrationto a subject; particularly hypothyroid subjects. Exemplary thyroidhormones are, e.g., thyroxine, triiodothyronine, synthroid and otherthyroxine analogs. The thyroid hormones are given daily, once a day,suitably in the morning after waking. Suitably, the thyroid hormone isgiven at dosage levels ranging from about 0.1 to about 0.4 milligramsper day, preferably from about 0.2 to about 0.35 milligrams per day.

In the practice of this invention, the dopamine agonist, orprolactin-inhibiting compound, and prolactin stimulator are administereddaily to a subject orally or by subcutaneous, intravenous orintramuscular injections, at different times of day, to alter theprolactin rhythm from that of a lean subject to that of an obese subjectof the same species, or as is most often the objective to alter theprolactin rhythm from that of an obese subject to that of a lean subjectof the same species. In treating a subject to alter, reset, and phaseshift the prolactin rhythm from that of an obese subject to that of alean subject, administration of the dopamine agonist and prolactinstimulator can not only be employed to reduce body fat stores, orobesity, in an obese subject, but also to reduce insulin resistance,hyperinsulinemia or hyperglycemia, or both hyperinsulinemia andhyperglycemia, in a subject obese or lean, exhibiting any one, or all ofthese symptoms desirable of change. In carrying out this process, whereit is desired to modify, phase shift, and reset the prolactin rhythm ofa subject to that of a lean animal, to reduce body fat stores if thesubject is obese, increase sensitivity response to insulin whether thesubject is lean or obese, and suppress hyperinsulinemia orhyperglycemia, or both, whether the subject is lean or obese, thedopamine agonist is administered in daily dosage amount sufficient todecrease, or reduce hormonal prolactin secretion in the blood of thesubject at a time or just after the time of day corresponding to thatwhen the prolactin level in the blood of a lean insulin sensitivesubject is at a peak, and the prolactin stimulator is administered indosage amount sufficient to increase hormonal prolactin secretion in theblood of the subject at a time or near the time of day when theprolactin level in the blood of a lean insulin sensitive subject is atits lowest point, or point of maximum depression; this occurring justbefore the prolactin level rises to a peak in a lean insulin sensitivesubject. Thus, a prolactin-inhibiting compound, preferably anergot-related prolactin-inhibiting compound, is administered to asubject exhibiting any one or more of the symptoms desirable of change,e.g., obesity, insulin resistance, hyperinsulinemia or hyperglycemia ata time of day when plasma prolactin levels are low in lean insulinsensitive subjects of the same species. Exemplary ofprolactin-inhibiting, ergot-related compounds are2-bromo-alpha-ergocryptine; 6-methyl-8 beta-carbobenzyloxy-aminoethyl-10alpha-ergoline; 8-acylaminoergolenes, such as 6-methyl-8alpha-(N-acyl)amino-9-ergoline and 6-methyl-8alpha-(N-phenylacetyl)amino-9-ergoline; ergocornine;9,10-dihydroergocornine; and D-2-halo-6-alkyl-8-substituted ergolines,e.g., D-2-bromo-6-methyl-8-cyanomethylergoline. Moreover, the non-toxicsalts of the prolactin-inhibiting ergot-related compounds formed frompharmaceutically acceptable acids are also useful in the practice ofthis invention. Bromocriptine, or 2-bromo-alpha-ergocryptine, has beenfound particularly useful in the practice of this invention. A prolactinstimulator is administered to the same subject just before that time ofday when daily plasma prolactin levels are highest in lean insulinsensitive subjects of the same species (i.e., before the onset ofsleep). Exemplary of prolactin stimulators are dopamine antagonists,i.e., metoclopramide, haloperidol, pimozide, phenothiazine, sulpiride,chloropromazine and serotonin agonists, i.e. MAO inhibitors, e.g.pargyline, synthetic morphine analogs, e.g. methadone, antiemetics, e.g.metoclopramide, antipsychotics, e.g. sulpiride, estrogens and others,e.g., tryptophan and 5-hydroxy-tryptophan.

In the treatment of an animal, or human subject, the stores of body fatcan be depleted or increased, the treatments continued until the storesof body fat are stabilized at an optimum or near optimum level dependenton the level of body fat stores desired in the subject, for timesufficient that on termination of the treatment the prolactin rhythm,and preferably both the prolactin and glucocorticosteroid rhythms, arereset to maintain on a long term basis the reduced, or increased, bodyweight stores. In humans, the objective is almost invariably to reducebody fat stores. In humans, the objective is almost invariably to reducebody fat stores, and obesity. It has been established that arelationship exists between obesity and insulin resistance, and thatobesity can lead to increased insulin resistance. Likewise, it has beenestablished that the circadian rhythms of plasma prolactin andglucocorticosteroid concentrations, respectively, differ in lean and fatanimals as well as in insulin sensitive animals and animals that areinsulin resistant (decreased insulin stimulated glucose disposal). In afat animal, prolactin will reach a peak level at a given hour of a 24hours period (in a human, usually near midday), and the prolactin levelof a less animal at another time of day (in a human usually duringsleep). In a lean animal the glucocorticosteroids, e.g., cortisol, willpeak during a 24 hour period at a given hour (generally at a timedifferent from that of prolactin); in a human generally several hoursafter waking. Thus, the phase relations of the coritsol and prolactinrhythms differ in lean and fat animals. The peak periods of prolactinand glucocorticosteroid production, respectively, may differ to someextent between males and females of any given species. In carrying outthe invention process, a daily dosage of a dopamine agonist, orprolactin inhibitor, is given to an obese subject shortly after thenormal time of day that the prolactin is at its peak in a lean insulinsensitive subject of the same species and sex, and daily dosages of aprolactin stimulator are given to the same obese subject (in conjunctionwith the prolactin inhibitor) shortly before the normal time of day thatthe prolactin is at its peak in a lean insulin sensitive subject of thesame species and sex, to produce a body (at weight reduction in theobese subject. Such treatment will, if continued over a sufficientperiod, reset on a long term or permanent basis the phase of the neuraloscillation for the prolactin rhythm, or the phases of the neuraloscillations for both the prolactin and glucocorticosteroid rhythms inthe obese insulin resistant subject to that present in a lean insulinsensitive subject. The obese subject, on initiation of the treatmentwith the dopamine agonist, or prolactin inhibitor in conjunction withthe prolactin stimulator, will lose body fat stores, and the body fatdeposits of the obese subject on continuation of the treatments on adaily basis will drop to and stabilize at that of a lean subject of thesame species. On discontinuing the daily treatments, the rise and fallof the prolactin, or prolactin and glucocorticosteroid levels in theblood of the treated patient on a daily basis will correspond to that ofa lean insulin sensitive subject of the same species, and for a periodof long duration. The effect of resetting the prolactin, or prolactinand glucocorticosteroid rhythms, in this manner in a subject exhibitingany one or more of the symptoms desirable of change, i.e., insulinresistance, hyperinsulinemia or hyperglycemia, whether the subject islean or obese (and loses body fat stores) also increases the sensitivityof the cells of the subject to insulin, reduces hyperinsulinemia orhyperglycemia, or both, and thus alters long term pathologies which arecharacteristics of the onset of Type II diabetes.

In treating vertebrates, generally, dosages of the dopamine agonist, andprolactin stimulator, respectively, are each given, generally once aday, on a daily basis, generally over a period ranging from about 10days to about 150 days. The dopamine agonist is given daily at dosagelevels ranging from about 3 micrograms to about 100 micrograms,preferably from about 8 micrograms to about 20 micrograms, per pound ofbody weight, and the prolactin stimulator is given daily at dosagelevels ranging from about 10 micrograms to about 100 micrograms,preferably from about 20 micrograms to about 50 micrograms, per pound ofbody weight to modify, or alter, and continued for a time sufficient toreset the circadian plasma prolactin rhythm.

In treating humans, the dopamine agonist, or prolactin inhibitor, isgenerally given at daily dosage levels ranging from about 3 microgramsto about 20 micrograms, preferably from about 4 micrograms to about 12micrograms, per pound of body weight, and the prolactin stimulator isgenerally given at daily dosage levels ranging from about 10 microgramsto about 100 micrograms, preferably from about 20 micrograms to about 50micrograms, per pound of body weight. Such treatments continued over aperiod of time ranging from about 30 days to about 60 days will modifyand reset the lipid and glucose metabolism of the obese person to thatof a lean person, if given to an obese person daily to that theprolactin inhibitor is given just a short period after the typical dailypeak of plasma prolactin concentration in a lean person and theprolactin stimulator is given a short period before plasma prolactinpeaks in a lean person. Body fat deposits, inclusive of adipose,arterial wall and plasma fat, within the obese person will be reduced,leveled out and maintained after the treatments are discontinued at thatof a lean person, over an extended period of time. A person showing theeffects of insulin resistance, or hyperinsulinemia and/or hyperglycemia,or both insulin resistance and hyperinsulinemia and/or hyperglycermia,treated with the dopamine agonist, or prolactin inhibitor, and aprolactin stimulator at similarly appropriate times of day, will becomemore sensitive to insulin (i.e., will have a lower insulin resistance),and the effects of hyperinsulinemia and/or hyperglycemia will be reducedon a long term basis. The injections of the dopamine agonist, orprolactin inhibitor, and prolactin simulator, in this manner will thusreset the phase relations of the two neural oscillations and theirmultiple circadian expressions to alter metabolism on a long term basis,if not permanently. In other words, there will be as a result of thetimed daily dosages of the dopamine agonist, or prolactin inhibitor, andprolactin stimulator, a long term reversal of the major pathologiesgenerally associated with the development of Type II diabetes. Thelevels of body fat stores, plasma insulin concentrations, insulinresistance, and hyperglycemia, or all of these pathologies can bereduced on a long term basis by such treatment, or treatments, from thehigh levels often found in obese, hyperinsulinemic person to that of themuch lower and much more desirable levels found in lean euinsulinemicpersons.

The dopamine agonist is administered to a subject, particularly a human,exhibiting symptoms to be controlled at a time, or just after the timethe prolactin concentration reaches its peak in the plasma of a leansubject, particularly a lean insulin sensitive subject, generally withinabout 2 hours to about 8 hours, preferably within about 4 hours to about6 hours after the peak would occur in a lean subject, particularly alean insulin sensitive subject. The prolactin stimulator is administeredat a time just before the plasma prolactin rhythm found in a leansubject reaches its peak, generally from about 2 hours to about 4 hours,preferably from about 2 hours to about 3 hours, before the plasmaprotein has reached it peak in a lean person. Administration of theprolactin stimulator just before sleep has been found highlysatisfactory.

The responsiveness of the timed daily treatment with the dopamineagonist and prolactin stimulator can be further improved by theadministration of daily dosages of thyroid hormones, particularly in thetreatment of hypothyroid subjects or subjects whose blood during certaintimes of the year appear deficient in thyroid hormones. It is known,e.g., that the circadian rhythm of response to prolactin depends onadequate thyroid hormone (John, Meier and Bryant, Physiological Zoology45, pp. 34-42, 1972); and that the circadian rhythms of cortisol andprolactin responses are also dependent on thyroid hormone (Meier,Endocriminology 98, pp. 1474-1479, 1976; Ottenweller and Hedge, LifeSciences 28, pp. 1023-1040, 1981). Studies have shown that the furtheradministration of thyroid hormones on a daily basis with the dopamineagonist and prolactin stimulator in crease the responsiveness of manyhypothyroid, near hypothyroid, and seasonally hypothyroid subject typesto such treatments. It is accordingly a further preferred feature ofthis invention to administer once a day on a daily basis, besides thedopamine agonist and prolactin stimulator, thyroid hormone at dosagelevels ranging from about 0.1 milligrams to about 0.4 milligrams,preferably from about 0.2 milligrams to about 0.35 milligrams, thelevels of body fat, plasma triglyceride, plasma cholesterol and thesymptoms, or pathologies associated with Type II diabetes can be loweredon a long term basis by such treatment; and the treatment rendered moreeffective in hypothyroid individuals.

In terms of the human subject, "obesity can be defined as that bodyweight over twenty percent above the ideal body weight for a givenpopulation" (R. H. Williams, Textbook of Endocrinology, 1974, pp.904-916). The time of day when the prolactin and glucocorticosteroidlevels, respectively, will peak in the blood of humans during the daydiffers between obese subjects and lean subjects, and the peak in eachtype of subject can be readily determined by measurement of the fat andlean specimens, as defined. In other animal species what constitutesobese and lean members, respectively, of a species can be readilydetermined by body weight patterns correlated with the prolactin andglucocorticosteroid levels, respectively, in the plasma of lean andobese members, respectively. The levels differ between members of thedifferent species, but among members of the same species there is closecorrelation between prolactin and glucocorticosterone levels,respectively, at certain times of the day dependent on the obesity orleanness of a given specimens.

These and other features of the invention will be better understood byreference to the following information and data of experimental workwith animals and humans. In the examples the terminology "LD" refers tothe light/dark cycle, the first number following the expression LDrefers to the hours of light, and the second to the hours of darkness inthe cycle. Thus LD 14:10 refers to a cycle having 14 hours of light and10 hours of darkness, and this period of the day is expressed in termsof 2400 hours. The letter n refers to the number of animals in a group."BE" designates body weight, g represents grams, mg representsmilligrams, and "ub" is an expression of micrograms.

In the following examples, data are given which show the altered phaserelationships of the circadian rhythms of plasma corticosteroid andprolactin concentrations; changes beneficial in the treatment ofdiabetics.

EXAMPLE 1

A 44 year old obese woman weighing 198 pounds was given bromocriptinetablets (2.5 mg/day), taken orally, shortly after waking in the morning,and metoclopramide tablets (10 mg/day), taken orally, just before sleeplate at night. After 6 weeks of treatment, body weight was reduced by 5pounds without dieting or increased exercise. The percentage body fardetermined by skinfold measurements was reduced from 35.4 to 32.3. Thisreduction is equivalent to a loss of 7.7 pounds of body fat, from 70.0pounds to 62.3 pounds. Loss of fat exceeding loss of body weight is ageneral characteristic of this treatment that sharply differentiates itfrom diet programs in which considerable protein, carbohydrate and wateris lost in addition to fat.

EXAMPLE 2

A hypothyroid 58 year old woman who was mildly obese responded poorly tobromocriptine (1.25 mg) taken orally daily 2 hours after waking for 3months. A change in treatment to a combination of bromocriptine andmetoclopramide (Reglan), a prolactin stimulator, in conjunction with anincrease of thyroid hormone (Synthroid) from 0.2 to 0.35 mg daily,produced dramatic losses in both body fat stores and body weight. Oraldosages of bromocriptine (1.25 gm) were taken daily 1 hours after wakingand metoclopramide (5 mg) was taken orally immediately before sleep.Synthroid was taken orally (0.35 mg/day) within 2 hours after waking.After 6 weeks, body weight was reduced from 161 to 145 pounds without arestriction on food consumption or increased exercise regimen. Body fatstores determined by skinfold measurements were reduced by 8.5 pounds,from a total fat content of 53.8 pounds to 45.3 pounds. The subjectclaimed she had not been so lean nor weighted to little in 22 years.Further decreases in body fat and body weight were evident after 20weeks of treatment. Weight was reduced from 161 lbs (initial) to 125 lbsand fat was reduced by a total of 20.6 lbs. In addition, plasmaconcentrations of total cholesterol and triglyceride were reduced bysuch treatment after 20 weeks, the initial and final cholesterol levelswere 237 and 152 mg/dl, respectively. The initial and final triglyceridelevels were 1191 and 161 mg./dl. respectively. This combination ofprolactin inhibitor (bromocriptine), prolactin stimulator(metoclopramide)and thyroid hormone has been found especially useful forresetting circadian rhythms in hypothyroid individuals who have rhythmsof low amplitude that are resistant to resetting by bromocriptine alone.

EXAMPLE 3

A 57 year old obese woman was given orally 1.25 mg bromociptine dailyone hour after waking and 10 mg metoclopramide shortly before sleep.After 2 weeks body weight was reduced from 194 to 189 pounds andpercentage body fat, determined from skinfold measurements, was reducedfrom 39.5 to 38.1. The fat lost, then, in 2 weeks was 4.6 pounds,accounting for almost all of the body weight loss.

EXAMPLE 4

A 63 years old obese woman was given orally 1.24 mg bromocriptine dailyat one hour after waking and 2.5 mg bromocriptine 6 hours after waking.Metociopramide (10 mg) was given orally immediately before sleep. After19 days, percentage body fat, determined by skinfold measurements, wasreduced from 37.1 to 35.5. This is a loss of 2.1 pounds of fat withoutfood restriction, increased exercise or loss of body weight.

EXAMPLE 5

A 60 year old obese woman with Type II diabetes was given orally 1.25 mgbromocriptine daily at one hour after waking and 10 mg metoclopramideimmediately before sleep. After 6 weeks, body fat was reduced from 108.3lbs (initial) to 97.9 lbs. Fasting blood glucose levels were reducedfrom 126 mg/dl (initial) to normal levels (near 100 mg/dl). Furthermore,the daily dose of the hypoglycemic drug the took for treatment ofdiabetes (micronase) was reduced from 5.0 to 2.5 mg midway during thebromocriptine/metoclopramide treatments.

EXAMPLE 6

As obese 55 year old man weighing 285 pounds with Type II diabetes wasgiven orally 2.5 mg bromocriptine daily one hour after waking and 10 mgmetoclopramide immediately before sleep. He lost 11 pounds of fat during8 weeks of treatment. Fasting blood glucose levels were 180 mg/dl priorto treatment. After 4 weeks of treatment, blood glucose levels were nearnormal (100 mg/dl) and diabetic treatment with a hypoglycemic drug(micronase) was discontinued. After 8 weeks of bromocriptine andmetoclopramide treatment, the fasting glucose was 104 mg/dl.

EXAMPLE 7

Three post menopausal women (Subjects A, B and C) with high initiallevels of body fat (40.6, A; 37.1, B; and 39.5, C; % body weight), asindicated by skinfold measurements, were treated orally with 1.25 mgbromocriptine taken within one hour of waking and 5 mg metoclopramidetaken immediately before sleep. Body fat was reduced by 5.8 lbs after 7weeks (Subject A), 5.1 lbs after 5 weeks (Subject B) and 6.5 lbs after 4weeks (Subject C).

EXAMPLE 8

Two control groups of adult human subjects, a first control group ofseven patients was treated daily through the warm months withbromocriptine alone, and a second control group of ten patients wastreated during the same period daily with both bromocriptine andmetoclopramide. In the first control group the bromocriptine wasadministered once a day orally in dosage levels of 1.25 mg and 2.5 mg.respectively, in the morning just after waking. The second group wassimilarly treated, except that each person in this group wasadditionally given daily by mouth at bedtime 10 mg of themetoclopramide. The treatment were continued daily over periods rangingup to 16 weeks. During the period of treatment the body fat content ofeach patient was determined from skinfold measurements (suprailliac,subscapular, triceps and biceps). The number of weeks of treatment, thetotal decrease in body fat (lbs.) during the period, and the averagebody fat loss (lbs.) per week for each individual of the two groups aregiven in the Table.

                  TABLE                                                           ______________________________________                                        Reductions of Body Fat in Adult Human Subjects.sup.1                          Treated with Bromocriptine Alone, and                                         Both Bromocriptine and Metoclopramide, Respectively                                                         Decrease                                                                             Fat Loss                                           Initials of                                                                              Weeks of in Body                                                                              Per                                      Treatment Subjects   Treatment                                                                              Fat (lbs)                                                                            Week (lbs)                               ______________________________________                                        Bromocriptine                                                                           PC         9        3.5    0.39                                               JL         12       5.3    0.44                                               FB         6        8.8    1.47                                               JA         6        1.7    0.28                                               JW-1       8        5.1    0.64                                               JW-2       8        1.9    0.24                                               BH         6        2.0    0.33                                               Mean ± SEM                                                                            7.8 ± 2.2                                                                           4.0 ± 2.6                                                                         0.54 ± 0.17.sup.                      Bromocriptine +                                                                         MM         6        4.6    0.77                                     Metoclopramide                                                                          AM-1       16       16.5   1.03                                               TC         3        6.4    2.13                                               MH         6        3.1    0.52                                               BR         3        3.7    1.23                                               WH         6        3.1    0.52                                               AM-2       5        5.1    1.02                                               LG         4        6.5    1.62                                               HG         5        3.7    0.74                                               JW         8        5.8    0.72                                               Mean ± SEM                                                                            6.2 ± 3.1                                                                           5.9 ± 3.3                                                                         0.95 ± 0.16.sup.2                     ______________________________________                                         .sup.1 Mean body weight was 175 lbs and mean % body fat, initially, was       33.5 (58.6 lbs fat).                                                          .sup.2 This value differs (p < 0.05; Student's t) from that of subjects       treated with bromocriptine, alone                                        

These data show that the average body fat loss per week for the grouptreated with both bromocriptine and metoclopramide was essentiallydouble that of the group treated with bromocriptine alone. Moreover, thetotal decrease in body fat over the period was higher for the grouptreated with both bromocriptine and metoclopramide. It was found thatthe treatment of a subject with both bromocriptine and metoclopramidevis-a-vis treatment of a subject with bromocriptine alone is moreeffective during the summer months than during the winter months.

The data show that metabolic states are regulated at least in part by aninteraction of circadian neuroendocrine rhythms. It is believed that thedaily rhythms of cortisol and prolactin are individual expression of twoseparate circadian systems and that the daily injections of thesehormones can reset the phase relations of these two systems. Thus, in ahamster model it has been found that the 0-hour relation resets thecircadian oscillations into a pattern that maintains the lean, insulinsensitive state and the 12-hour relation permits retention of a patternthat maintains the obese, insulin resistant state. The effects of timedinjections of a dopamine agonist, or prolactin-inhibiting compound, ithas been found are long lasting. Apparently once reset, the phaserelation of the two circadian oscillations tends to maintain its siteredpattern.

Changes in the phase relations of two circadian neuroendocrineoscillations are evidenced by changes in the phase relations of theircircadian expression. This expectation is fulfilled respecting plasmaglucocorticosteroid and prolactin rhythms. In several species examined,the phase relations of the two hormone rhythms differ in lean and fatanimals.

The phase relation between the circadian rhythm of plasma insulinconcentration and the rhythm of lipogenic responsiveness to insulin isshown to differ in lean and fat animals. Whereas the daily interval oflipogenic responsiveness remains near light onset, the phase of theinsulin rhythm varies markedly. The peak concentration of insulin, e.g.occurs near light onset in obese female hamsters held on short daylengths. That is, the daily peaks of the lipogenic stimulus (i.e.,insulin) and the lipogenic response to insulin coincide in fat animalsand not in lean animals.

The phase relations of both prolactin and insulin rhythms at well as therhythms of tissue responses to the hormones are important elements inthe regulation of lipogenesis. Phase malfunctions in these and perhapsother rhythms may also account for insulin resistance.

It is apparent that various modification and changes can be made withoutdeparting the spirit and scope of this invention.

Having described the invention, what is claimed is:
 1. A method fortreating a metabolic condition selected from the group consisting ofinsulin resistance, hyperinsulinemia, hyperglycemia, and glucosetolerance in an animal or human subject afflicted with said metaboliccondition, the method comprising:administering to said subject aneffective amount of a prolactin stimulatory compound on a timed dailybasis.
 2. The method of claim 1 wherein delivery of said prolactinstimulatory compound is confined to the period during the day after thetime at which the serum prolactin concentration of lean,insulin-sensitive subjects of the same species reaches its lowest leveland prior to the time of day when said prolactin concentration reaches apeak in lean, insulin-sensitive subjects of the same species.
 3. Amethod for altering body fat stores in an animal or human subject inneed of such treatment comprising:delivering to said subject aneffective amount of a prolactin stimulatory compound on a timed dailybasis.
 4. A method for adhering body weight in an animal or humansubject in need of such treatment comprising:delivering to said subjectan effective amount of a prolactin stimulatory compound on a timed dailybasis.
 5. The method of claim 3 wherein said delivery of said prolactinstimulatory compound is confined to the period during the day after thetime at which the serum prolactin concentration of lean,insulin-sensitive subjects of the same species reaches its lowest leveland prior to the time of day when said prolactin concentration reaches apeak in lean, insulin-sensitive subjects of the same species, therebydecreasing body fat stores in said subject.
 6. The method of claim 3wherein said delivery of said prolactin stimulatory compound is confinedto the period during the day 4 to 8 hours after the time of day at whichthe serum prolactin concentration of lean, insulin-sensitive subjects ofthe same species reaches a peak, thereby increasing body fat stores insaid subject.
 7. The method of claim 4 wherein said administration ofsaid prolactin stimulatory compound is confined to the period during theday after the time at which the serum prolactin concentration of lean,insulin-sensitive subjects of the same species reaches its lowest leveland prior to the time of day when said prolactin concentration reaches apeak in lean, insulin-sensitive subjects of the same species, therebydecreasing the body weight of said subject.
 8. The method of claim 4wherein said delivery of said prolactin stimulatory compound is confinedto the period during the day 4 to 8 hours after the time of day at whichthe serum prolactin concentration of lean, insulin-sensitive subjects ofthe same species reaches a peak, thereby increasing the body weight ofsaid subject.